While examples of therapeutic drugs against the acquired immunodeficiency syndrome (AIDS) caused by an infection with the human immunodeficiency virus (HIV) include a reverse transcriptase inhibitor and a protease inhibitor, therapeutic effectiveness of those drugs has been lost due to the emergence of drug resistant HIV mutants (see, for example, Saishin Igaku, Vol. 53, No. 9, p. 2031 (1998)). Also, the polypharmacy using the combination of such drugs has such disadvantages that it requires many conditions to be observed in administration, that it is complex, that it needs many kinds of drugs to be administered, and that it causes various side effects (see, for example, Nikkei Science, October, p. 29 (1998)). Moreover, particularly in case of using the protease inhibitor, it is known that the probability of causing emergence and screening of the resistant strain will increase unless the administration of approximately 100% of the drugs is kept, in spite of the complex administration method and many side effects thereof (see, for example, Molecular Medicine, Vol. 36, No. 9, p. 1012 (1999)).
Alternatively, development of vaccine has been attempted because many viral diseases were destroyed or remarkably weakened by vaccines in the past. However, this is considered to be extremely difficult since mutations are occurred frequently in HIV (see, for example, Nikkei Science, October, p. 42 (1998)).
Although several kinds of compounds having an anti-HIV effect have been reported as described above, it is now strongly desired to develop a novel antiviral drug which has excellent anti-retrovirus effect, is capable of opposing to the expression of the resistance, and which has little toxicity and causes little side effect, thereby allowing long term administration.
Chemokines is one kind of cytokine which renders chemotaxis to leukocytes, and is a secretory protein. Chemokine is classified into CXC-chemokine, CC-chemokine, C-chemokine, CX3C-chemokine according to the cysteine (Cys) sequence at N-terminal, and the total number thereof is said to be about 30. The chemokine receptor includes several sub types. Among them, it is known that the CXCR4 which is a ligand for CXC-chemokine SDF-1 is utilized as a coreceptor on infection to a host cell of T cell-directive HIV (see, for example, Science, 272, 872 (1996) and Nature, 382, 829 (1996)). The HIV invades through binding to the CXCR4 on the surface of a host cell of an envelope protein gp120. That is, the drug having antagonism against the CXCR4 is expected as an anti-HIV drug based on a novel mechanism of invasion inhibition, and there have been reported three low molecular compounds as such drugs: AMD3100 (see, for example, J. Exp. Med, 186, 1383 (1997), T22 (see, for example, J. Exp. Med, 186, 1389 (1997)), and ALX40-4C (see, for example, J. Exp. Med, 186, 1395 (1997)).
On the other hand, it has been elucidated that the CXCR4 associates with various diseases besides HIV infection. For example, there has been reported its association with rheumatic disease (see, for example, WO 00/06086), cancer metastatic disease (see, for example, Nature, 410, 50 (2001)), etc.
As a therapeutic drug for such diseases, it is strongly desired to develop a novel low-molecular drug which has CXCR4 antagonism, and which has little toxicity and causes little side effect, thereby allowing long term administration.